Acrylates, typically poly(methyl methacrylate) (PMMA), are bioinert materials commonly used to repair and augment spinal compression fractures and to fixate hip and knee implants. Since these materials have a Young's modulus that is much higher than that of human cancellous bone, they may affect the biomechanics negatively, which may promote fractures in the tissues adjacent to the augmented one. The development of PMMA cement with a lower modulus is highly desirable since it could reduce the incidence of subsequent complications, such as fractures. Further tailoring the Young's modulus by small changes in chemical composition, would give the possibility to adapt the cement to e.g. the degree of osteoporosis of a certain patient, which would make the cement patient-specific. Physical or chemical modification of the material would give the possibility to control its Young's modulus.
Various approaches to produce low-modulus PMMA bone cements have been documented.
One approach is to induce porosity in the material. A porous material could present a lower Young's modulus and also allow for a certain bone ingrowth. It has been shown that porous polymeric scaffolds may support osteoblast differentiation and subsequent bone formation (Shimko, White, et al. 2003).
Moreover, pores may act as drug reservoirs. The introduction of drugs into bone cements is of great importance in order to help the patients to recover upon surgery and to obtain the maximum benefit out of the cement. Drugs, such as bisphosphonates, may be beneficial to patients suffering from osteoporosis, due to the importance of these drugs in bone regeneration. Moreover, antibiotics, such as vancomycin, can help avoid possible infections at the site of injection. A porous structure may help to control the release of previously mentioned drugs or other types of growth factors from the material.
Currently, drugs can be directly mixed into the PMMA powder and thereby incorporated into the cement. This approach, however, limits the ability to control the release of drugs into the body, since it principally depends on the relative surface area of the total material injected. For instance, porous PMMA cement has been prepared by using water-soluble porogen salts, such as NaCl (Shimko and Nauman 2007). Porogen leaching is a common technique to create porous polymeric materials. In this example, the salt is added during the mixing step and it remains intact during the polymerization process. Upon setting, the salt is gradually dissolved out of the polymer, leaving pores behind. However, methods such as porogen leaching are not applicable to certain procedures, such as vertebroplasty.
Similarly, other studies (Shimko and Nauman 2007; van Mullem, de Wijn, et al. 1988) used an aqueous solution based on carboxymethyl cellulose to create a porous PMMA. This material has been successfully used in craniofacial surgery in its malleable form (Bruens, Pieterman, et al. 2003) but there are no reports on its usage while still being in the injectable stage.
The addition of a sodium hyaluronate solution has also been proposed to control the modulus and the porosity of PMMA bone cements (Boger, Bisig, et al. 2008; Boger, Bohner, et al. 2008). The sodium hyaluronate solution acts as a pore-forming phase due to its immiscibility. Unfortunately, it was later reported (Beck and Boger 2009) that this method gave rise to unacceptably high release of polymer powder particles. Some methods exist to induce porosity in PMMA using oils. Such procedures are described in detail in U.S. Pat. No. 4,594,207 and international application publication WO90/05007. However, these methods involve heating above the critical temperature of the mixture and these values are reported to be above 150° C. Such high temperatures are not applicable to injectable formulations and are intolerable for in vivo applications.
Another simple approach in order to decrease the modulus of PMMA bone cements may be their chemical modification, namely, copolymerization or grafting with somewhat more flexible species containing relatively long chains. These long chains could act as spacers between the polymer chains, somewhat lowering the glass transition temperature and facilitating the chain motion, which would result in a lower Young's modulus. Large molecules, may also act as physical spacers/plasticizers, if not grafted to the main polymer chain or network. The addition of plasticizers would also result in a lower Young's modulus. Chemical or physical modifiers can for instance be obtained from natural sources.
Polymers from renewable sources have quickly emerged due to their relatively low-cost and unique properties (Sehina Güner, Ya{hacek over (g)}ci, et al 2006). Natural oils, which consist mainly of triglycerides, can be obtained from a wide variety of renewable sources. Oil is thereby referred to as a triglyceride that is liquid at room temperature. Moreover, a triglyceride is obtained upon esterification of a glycerol molecule with three fatty acids. Most fatty acids are unsaturated, which means that they contain one to several double bonds in their chemical structure. These double bonds are susceptible to attack by free radicals, making these compounds able to be incorporated into the polymer during radical polymerization of PMMA.
Copolymerization of unsaturated fatty acids and their esters with unsaturated compounds is described in U.S. Pat. No. 2,574,753. However, their method is bulk polymerization and involves heating up the reactants to relatively high temperatures, which are not suitable for in vivo applications.
Natural oils have been used to fabricate interpenetrating polymer networks based on polyurethane and poly(methyl methacrylate). However, these synthesis methods also require relatively long polymerization times and high temperatures (Oliveira et al. 2004; Kong and Narine 2008), which are not suitable for in vivo applications.
Oleic acid derivatives such as 4-N,N-dimethylaminobenzyl oleate and oleyloxyethyl methacrylate have been used as total substitute for N,N-dimethyl-p-toluidine and partial substitute for methyl methacrylate, respectively. These formulations, although with improved handling properties, were not intended to lower the Young's moduli of the materials, whose values were between 1.20 and 3.58 GPa (Vázquez et al. 2001).
Another study (Lam et al. 2010) has shown that the incorporation of up to 20 wt % linoleic acid functionalized strontium-substituted hydroxyapatite particles, can lower the modulus down to 1800 MPa (12% respect to the control). Additionally, incorporation of up to 15 vol % linoleic acid substituting the monomer, can reduce the modulus down to 774 MPa (43% respect to the control). However, these particles are produced through a relatively complicated method and the researchers reported decreased cell viability due to unconverted monomer for this formulation.
WO 2004/071543 claims the use of a third hydrophobic component, such as fatty acids and other triglycerides, as possible solvents for organic radiopaque agents. However, the third component in this formulation is not intended to react with the PMMA or to be covalently incorporated into the cement but washed off from the cement instead. In fact, it is mixed in after the mixing of the powder and the liquid. US 2006/0293407 and US 2007/0031469 describe the use of esterified fatty acids as solvents for dyes.